Splicing dysregulation, caused by defects in RNA-binding splice factors including TDP-43, is considered a hallmark and potential driver of neuronal dysfunction and cognitive decline in Alzheimer?s (AD) and Related Dementia (ADRD). Although substantial evidence suggests that genetic causes of splicing dysfunction are not limited to neuronal cells, splicing defects in the BBB endothelium in AD and ADRD have not been examined. Defects in the BBB increase with age and early in the progression of AD and ADRD, where they contribute to disease progression. Through in vivo informatics and in vitro CRISPR screening, we identified TDP-43 and several other AD and ADRD associated splice factors as regulators of post-transcriptional splicing in the endothelium in response to sterile inflammation. Using a novel method to isolate endothelial nuclei from frozen banked human brain tissues, we identified reduced nuclear TDP- 43 levels in endothelial cells of the blood brain barrier (BBB) with age and in AD and ADRD patients. Furthermore, in a novel mouse model, we show that specific deletion of TDP-43 from the brain endothelium leads to leak across the BBB, and activation of the microvasculature and microglial cells. Here, we hypothesize that loss of nuclear TDP-43 in the endothelium contributes to defects in the BBB and microvasculature, and to AD and ADRD by affecting the splicing of pre-mRNA required for the maintenance of a quiescent endothelium. We propose to examine TDP-43 expression and splicing activity in the endothelium in human AD and ADRD, and the effect of loss of nuclear TDP-43 on disease progression in mouse models of AD and the ADRD Frontal temporal lobe dementia (FTLD). Furthermore, since our novel techniques will allow us an unprecedented view of the endothelium in AD and ADRD, we propose to extend our work on TDP-43 to broadly examine splicing alterations in the endothelium in these disease states, and use our established bioinformatics and in vitro screening approaches to determine whether defects in other endothelial splice factors also contribute to BBB dysfunction. The completion of this work will provide new insight into the contributions of post-transcriptional regulation by RNA-binding proteins to BBB defects, microvascular dysfunction and the progression of AD and ADRD.